Terminal deletion of chromosome 4 (4q deletion syndrome) is a rare genetic condition that is characterized by a broad clinical spectrum and phenotypic variability. Diagnosis of the distinct condition can be identified by conventional chromosome analysis and small deletions by novel molecular cytogenetic methods such as microarray comparative genome hybridization (aCGH). Prenatal diagnosis is challenging; to date 10 cases have been described. We report a prenatally diagnosed case of de novo 4q deletion syndrome confirmed by conventional karyotyping and FISH due to an elevated combined risk for Down syndrome and prenatal ultrasound findings. aCGH validated the diagnosis and offered exact characterization of the disorder. Cytogenetic and microarray results described a 4q32.1qter terminal deletion of the fetus. Prenatal ultrasound detected multiple nonstructural findings (micrognathia, choroid plexus cysts, echogenic fetal bowel, short femur, and cardiac axis deviation). Pregnancy was terminated at 20 weeks. In addition to the index patient, we reviewed the 10 prenatally published cases of 4q deletion syndrome in the literature and compared these with our results. We summarize the patients' characteristics and prenatal clinical findings. Alterations of maternal serum biochemical factors, an elevated combined risk for trisomies, and distinct ultrasonographic findings can often be observed in cases of prenatal 4q deletion syndrome and may facilitate the otherwise difficult prenatal diagnosis.

1.
Bianchi DW, Chiu RWK: Sequencing of circulating cell-free DNA during pregnancy. N Engl J Med 379:464-473 (2018).
2.
Bornstein E, Gulersen M, Krantz D, Cheung SW, Maliszewski K, Divon MY: Microarray analysis: first trimester maternal serum free β-hCG and the risk of significant copy number variants. Prenat Diagn 38:971-978 (2018).
3.
Caliebe A, Waltz S, Jenderny J: Mild phenotypic manifestations of terminal deletion of the long arm of chromosome 4: clinical description of a new patient. Clin Genet 52:116-119 (1997).
4.
Campbell JM, Williams J, Batcup G: Interstitial deletion of chromosome 4q diagnosed prenatally. J Med Genet 23:366-368 (1986).
5.
Chassaing N, Ragge N, Plaisancié J, Patat O, Geneviève D, et al: Confirmation of TENM3 involvement in autosomal recessive colobomatous microphthalmia. Am J Med Genet 170A:1895-1898 (2016).
6.
Ding H, Wu X, Boström H, Kim I, Wong N, et al: A specific requirement for PDGF-C in palate formation and PDGFR-α signaling. Nature Genet 36:1111-1116 (2004).
7.
Friedman JM: High-resolution array genomic hybridization in prenatal diagnosis. Prenat Diagn 29:20-28 (2009).
8.
Giuffrè M, La Placa S, Carta M, Cataliotti A, Marino M, et al: Hypercalciuria and kidney calcifications in terminal 4q deletion syndrome: further evidence for a putative gene on 4q. Am J Med Genet A 126A:186-190 (2004).
9.
Gonzalez C, Serrano MG, Lopez CB, Garcia-Riaño T, Barea Calero V, et al: CGH array and karyotype as complementary tools in prenatal diagnosis: prenatal diagnosis of a 4q derivative chromosome from maternal 4q;11q translocation. Fetal Pediatr Pathol 37:184-190 (2018).
10.
Häfner FM, Salam AA, Linder TE, Balmer D, Baumer A, et al: A novel locus (DFNA24) for prelingual nonprogressive autosomal dominant nonsyndromic hearing loss maps to 4q35-qter in a large Swiss German kindred. Am J Hum Genet 66:1437-1442 (2000).
11.
Hemmat M, Hemmat O, Anguiano A, Boyar FZ, El Naggar M, et al: Genotype-phenotype analysis of recombinant chromosome 4 syndrome: an array-CGH study and literature review. Mol Cytogenet 6:17 (2013).
12.
Hillman SC, McMullan DJ, Hall G, Togneri FS, James N, et al: Use of prenatal chromosomal microarray: prospective cohort study and systematic review and meta-analysis. Ultrasound Obstet Gynecol 41:610-620 (2013).
13.
Hsu Ty, Kung FT, Ou CY, Hsiao PY, Huang FJ, et al: Prenatal diagnosis of de novo interstitial deletion of proximal 4q by maternal serum screening for Down syndrome. Prenat Diagn 18:1323-1327 (1998).
14.
Keeling SL, Lee-Jones L, Thompson P: Interstitial deletion 4q32-34 with ulnar deficiency: 4q33 may be the critical region in 4q terminal deletion syndrome. Am J Med Genet 99:94-98 (2001).
15.
Kleeman L, Bianchi DW, Shaffer LG, Rorem E, Cowan J, et al: Use of array comparative genomic hybridization for prenatal diagnosis of fetuses with sonographic anomalies and normal metaphase karyotype. Prenat Diagn 29:1213-1217 (2009).
16.
Koppitch FC 3rd, Ramahi A, Quereshi F, Budev H, Perrin E, Evans MI: Prenatal diagnosis of and midtrimester pathology with karyotype 46,XY,del(4)(q22q26). A case report. J Reprod Med 35:182-186 (1990).
17.
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, et al: Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285-291 (2016).
18.
Manolakos E, Vetro A, Kefalas K, Rapti SM, Louizou E, et al: The use of array-CGH in a cohort of Greek children with developmental delay. Mol Cytogenet 3:22 (2010).
19.
Manolakos E, Kefalas K, Vetro A, Oikonomidou E, Daskalakis G, et al: Prenatal diagnosis of two de novo 4q35-qter deletions characterized by array-CGH. Mol Cytogenet 6:47 (2013).
20.
Novo-Filho GM, Montenegro MM, Zanardo EA, Dutra RL, Dias AT, et al: Subtelomeric copy number variations: the importance of 4p/4q deletions in patients with congenital anomalies and developmental disability. Cytogenet Genome Res 149:241-246 (2016).
21.
Ockey CH, Feldman GV, Macaulay ME, Delaney MJ: A large deletion of the long arm of chromosome No. 4 in a child with limb abnormalities. Arch Dis Child 42:428-434 (1967).
22.
Rossi MR, DiMaio MS, Xiang B, Lu K, Kaymakcalan H, et al: Clinical and genomic characterization of distal duplications and deletions of chromosome 4q: study of two cases and review of the literature. Am J Med Genet A 149A:2788-2794 (2009).
23.
Russell Z, Kontopoulos EV, Quintero RA, DeBauche DM, Ranells JD: Prenatal diagnosis of a 4q33-4qter deletion in a fetus with hydrops. Fetal Diagn Ther 24:250-253 (2008).
24.
Scott F, Bonifacio M, Sandow R, Ellis K, Smet ME, McLennan A: Rare autosomal trisomies: important and not so rare. Prenat Diagn 38:765-771 (2018).
25.
Shao L, Shaw CA, Lu XY, Sahoo T, Bacino CA, et al: Identification of chromosome abnormalities in subtelomeric regions by microarray analysis: a study of 5,380 cases. Am J Med Genet A 146A:2242-2251 (2008).
26.
Srebniak MI, Diderich KE, Joosten M, Govaerts LC, Knijnenburg J, et al: Prenatal SNP array testing in 1,000 fetuses with ultrasound anomalies: causative, unexpected and susceptibility CNVs. Eur J Hum Genet 24:645-651 (2016).
27.
Strehle EM: Dysmorphological and pharmacological studies in 4q-syndrome. Genet Couns 22:173-185 (2011).
28.
Strehle EM, Bantock HM: The phenotype of patients with 4q-syndrome. Genet Couns 14:195-205 (2003).
29.
Strehle EM, Ahmed OA, Hameed M, Russell A: The 4q-syndrome. Genet Couns 12:327-339 (2001).
30.
Strehle EM, Gruszfeld D, Schenk D, Mehta SG, Simonic I, Huang T: The spectrum of 4q-syndrome illustrated by a case series. Gene 506:387-391 (2012a).
31.
Strehle EM, Yu L, Rosenfeld JA, Donkervoort S, Zhou Y, et al: Genotype-phenotype analysis of 4q deletion syndrome: proposal of a critical region. Am J Med Genet A 158A:2139-2151 (2012b).
32.
Tidrenczel Z, P Tardy E, Sarkadi E, Simon J, Beke A, Demeter J: Prenatally diagnosed case of Pallister‒Killian syndrome (in Hungarian). Orv Hetil 159:847-852 (2018).
33.
Townes PL, White M, Di Marzo SV: 4q-syndrome. Am J Dis Child 133:383-385 (1979).
34.
Tzschach A, Menzel C, Erdogan F, Istifli ES, Rieger M, et al: Characterization of an interstitial 4q32 deletion in a patient with mental retardation and a complex chromosome rearrangement. Am J Med Genet A 152A:1008-1012 (2010).
35.
Vlaikou AM, Manolakos E, Noutsopoulos D, Markopoulos G, Liehr T, et al: An interstitial 4q31.21q31.22 microdeletion associated with developmental delay: case report and literature review. Cytogenet Genome Res 142:227-238 (2014).
36.
Vona B, Nanda I, Neuner C, Schröder J, Kalscheuer VM, et al: Terminal chromosome 4q deletion syndrome in an infant with hearing impairment and moderate syndromic features: review of literature. BMC Med Genet 15:72 (2014a).
37.
Vona B, Müller T, Nanda I, Neuner C, Hofrichter MA, et al: Targeted next-generation sequencing of deafness genes in hearing-impaired individuals uncovers informative mutations. Genet Med 16:945-953 (2014b).
38.
Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, et al: Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 367:2175-2184 (2012).
39.
Xu W, Ahmad A, Dagenais S, Iyer RK, Innis JW: Chromosome 4q deletion syndrome: narrowing the cardiovascular critical region to 4q32.2-34.3. Am J Med Genet A 158A:635-640 (2012).
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